OBJECTIVE:Disorders of arousal (DoA) are characterized by an intermediate state between wakefulness and deep sleep, leading to incomplete awakenings from NREM sleep. Multimodal studies have shown subtle neurophysiologic alterations even during wakefulness in DoA. The aim of this study was to explore the brain functional connectivity in DoA and the metabolic profile of the anterior and posterior cingulate cortex, given its pivotal role in cognitive and emotional processing. METHODS:Fifteen consecutive patients with DoA (9 males, mean age 26.3 ± 7.7) and 15 age- and sex-matched healthy controls (8 males, mean age 25.8 ± 3.6) were enrolled. All participants underwent a protocol including sleep and psychological evaluation scales and multimodal brain MRI with resting-state functional MRI and 1H-MR spectroscopy. RESULTS:The independent component analysis disclosed an altered resting-state functional connectivity (FC) in the patients' sensory motor network, with a higher connectivity strength in opercular cortex, precuneus, occipital pole, and lingual gyrus. The seed-based analysis revealed a decreased FC between posterior cingulate cortex (PCC) and several cerebral areas. Finally, spectroscopic imaging revealed a reduced content of glutamine in the PCC (p < 0.001). INTERPRETATION:The increased connectivity in the sensory-motor network of DoA patients could constitute a "facilitatory medium" enhancing motor circuit activation, while the connectivity and metabolic alterations of PCC might represent a trait functional feature, contributing to a dysfunctional arousal process and the difficulty to reach a complete awareness during DoA episodes. In addition, these alterations at rest might be related to daytime impairment reported by patients, requiring new strategies for DoA management.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in the cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 8 severe de novo pdSNVs in genes not previously implicated in ASD (AGPAT3, IRX5, MGAT5B, RAB8B, RAP1A, RASAL2, SLC9A1, YME1L1) highlighted promising candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, although this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in ASD/NDD candidate genes not yet established. In conclusion, our study highlights promising ASD candidate genes and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

Background: Being able to differentiate mild cognitive impairment (MCI) patients who would eventually convert (MCIc) to Alzheimer’s disease (AD) from those who would not (MCInc) is a key challenge for prognosis. Objective: This study aimed to investigate the ability of sulcal morphometry to predict MCI progression to AD, dedicating special attention to an accurate identification of sulci. Methods: Twenty-five AD patients, thirty-seven MCI and twenty-five healthy controls (HC) underwent a brain-MR protocol (1.5T scanner) including a high-resolution T1-weighted sequence. MCI patients underwent a neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 2.3 years. At follow-up, 12 MCI were classified as MCInc and 25 as MCIc. Sulcal morphometry was investigated using the BrainVISA framework. Consistency of sulci across subjects was ensured by visual inspection and manual correction of the automatic labelling in each subject. Sulcal surface, depth, length, and width were retrieved from 106 sulci. Features were compared across groups and their classification accuracy in predicting MCI conversion was tested. Potential relationships between sulcal features and cognitive scores were explored using Spearman’s correlation. Results: The width of sulci in the temporo-occipital region strongly differentiated between each pair of groups. Comparing MCIc and MCInc, the width of several sulci in the bilateral temporo-occipital and left frontal areas was significantly altered. Higher width of frontal sulci was associated with worse performances in short-term verbal memory and phonemic fluency. Conclusions: Sulcal morphometry emerged as a strong tool for differentiating HC, MCI, and AD, demonstrating its potential prognostic value for the MCI population.

The topic of typical sex and gender difference in empathy is examined in both a developmental and neuroscientific perspective. Empathy is construed as a multi‐layered phenomenon with various degrees of complexity unfolding in ontogeny. The different components of empathy (i.e., affective, cognitive, and prosocial motivation) will be discussed as they interact and are expressed behaviorally. Significant sex/gender differences in empathy are discussed in relation to putative bottom‐up or top‐down processes underlying empathetic responses. The early onset and the pervasive presence of such sex/gender differences throughout the lifespan are further discussed in light of social and neurobiological modeling factors, including early socialization, brain's structural/functional variances, as well as genetics and hormonal factors.

Objectives: To explore the neuropsychological profile and the integrity of the olfactory network in patients with COVID-19-related persistent olfactory dysfunction (OD).Methods: Patients with persistent COVID-19-related OD underwent olfactory assessment with Sniffin' Sticks and neuropsychological evaluation. Additionally, both patients and a control group underwent brain MRI, including T1-weighted and resting-state functional MRI (rs-fMRI) sequences on a 3 T scanner. Morphometrical properties were evaluated in olfaction-associated regions; the rs-fMRI data were analysed using graph theory at the whole -brain level and within a standard parcellation of the olfactory functional network. All the MR-derived quantities were compared between the two groups and their correlation with clinical scores in patients were explored.Results: We included 23 patients (mean age 37 & PLUSMN; 14 years, 12 females) with persistent (mean duration 11 & PLUSMN; 5 months, range 2-19 months) COVID-19-related OD (mean score 23.63 & PLUSMN; 5.32/48, hyposmia cut-off: 30.75) and 26 sex-and age-matched healthy controls. Applying population-derived cut-off values, the two cognitive do-mains mainly impaired were visuospatial memory and executive functions (17 % and 13 % of patients). Brain MRI did not show gross morphological abnormalities. The lateral orbital cortex, hippocampus, and amygdala volumes exhibited a reduction trend in patients, not significant after the correction for multiple comparisons. The olfactory bulb volumes did not differ between patients and controls. Graph analysis of the functional olfactory network showed altered global and local properties in the patients' group (n = 19, 4 excluded due to artifacts) compared to controls. Specifically, we detected a reduction in the global modularity coefficient, positively correlated with hyposmia severity, and an increase of the degree and strength of the right thalamus functional connections, negatively correlated with short-term verbal memory scores.Discussion: Patients with persistent COVID-19-related OD showed an altered olfactory network connectivity correlated with hyposmia severity and neuropsychological performance. No significant morphological alter-ations were found in patients compared with controls.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We have performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 9 severe de novo pdSNVs in genes not previously implicated in ASD (RASAL2, RAP1A, IRX5, SLC9A1, AGPAT3, MGAT3, RAB8B, MGAT5B, YME1L1), highlighted novel candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, but this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in new ASD/NDD candidates. In conclusion, our study strengthens the role of BRSK2 and other neurodevelopmental genes in ASD risk, highlights novel candidates and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

We propose Rhythmic Relating for autism: a system of supports for friends, therapists, parents, and educators; a system which aims to augment bidirectional communication and complement existing therapeutic approaches. We begin by summarizing the developmental significance of social timing and the social-motor-synchrony challenges observed in early autism. Meta-analyses conclude the early primacy of such challenges, yet cite the lack of focused therapies. We identify core relational parameters in support of social-motor-synchrony and systematize these using the communicative musicality constructs: pulse; quality; and narrative. Rhythmic Relating aims to augment the clarity, contiguity, and pulse-beat of spontaneous behavior by recruiting rhythmic supports (cues, accents, turbulence) and relatable vitality; facilitating the predictive flow and just-ahead-in-time planning needed for good-enough social timing. From here, we describe possibilities for playful therapeutic interaction, small-step co-regulation, and layered sensorimotor integration. Lastly, we include several clinical case examples demonstrating the use of Rhythmic Relating within four different therapeutic approaches (Dance Movement Therapy, Improvisational Music Therapy, Play Therapy, and Musical Interaction Therapy). These clinical case examples are introduced here and several more are included in the Supplementary Material (Examples of Rhythmic Relating in Practice). A suite of pilot intervention studies is proposed to assess the efficacy of combining Rhythmic Relating with different therapeutic approaches in playful work with individuals with autism. Further experimental hypotheses are outlined, designed to clarify the significance of certain key features of the Rhythmic Relating approach.

Resting-state functional MRI has been increasingly implemented in imaging protocols for the study of functional connectivity in glioma patients as a sequence able to capture the activity of brain networks and to investigate their properties without requiring the patients' cooperation. The present review aims at describing the most recent results obtained through the analysis of resting-state fMRI data in different contexts of interest for brain gliomas: the identification and localization of functional networks, the characterization of altered functional connectivity, and the evaluation of functional plasticity in relation to the resection of the glioma. An analysis of the literature showed that significant and promising results could be achieved through this technique in all the aspects under investigation. Nevertheless, there is room for improvement, especially in terms of stability and generalizability of the outcomes. Further research should be conducted on homogeneous samples of glioma patients and at fixed time points to reduce the considerable variability in the results obtained across and within studies. Future works should also aim at establishing robust metrics for the assessment of the disruption of functional connectivity and its recovery at the single-subject level.

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.

In this review, we discuss the topic of intersubjectivity and its disruption in Autism Spectrum Disorder, both from a developmental and neuroscientific perspective. We present evidence of the impact of an early neurodevelopmental disorder on the blooming of intersubjective abilities. We propose the existence of a basic, pre-reflective social cognition that originates from the sensorimotor networks and is anchored to their teleological organization. We present neurophysiological evidence of its involvement in the direct understanding of three core elements of action: its category, its goal, and its dynamic contour. Finally, we discuss to which extent the disrupted development of brain neuroarchitecture and connectivity in Autism could also possibly impact on basic social cognition, thus preventing fluid, preverbal alignment with the others.

Myotonic dystrophy type 1 (DM1) is a genetic disorder caused by a (CTG) expansion in the DM protein kinase (DMPK) gene, representing the most common adult muscular dystrophy, characterized by a multisystem involvement with predominantly skeletal muscle and brain affection. Neuroimaging studies showed widespread white matter changes and brain atrophy in DM1, but only a few studies investigated the role of white matter metabolism in the pathophysiology of central nervous system impairment. We aim to reveal the relationship between the metabolic profile of parieto-occipital white matter (POWM) as evaluated with proton MR spectroscopy technique, with the visuoperceptual and visuoconstructional dysfunctions in DM1 patients. MR spectroscopy (3 Tesla) and neuropsychological evaluations were performed in 34 DM1 patients (19 F, age: 46.4 ± 12.1 years, disease duration: 18.7 ± 11.6 years). The content of neuro-axonal marker N-acetyl-aspartate, both relative to Creatine (NAA/Cr) and to myo-Inositol (NAA/mI) resulted significantly lower in DM1 patients compared to HC (p-values < 0.0001). NAA/Cr and NAA/mI correlated with the copy of the Rey-Osterrieth complex figure (r = 0.366, p = 0.033; r = 0.401, p = 0.019, respectively) and with Street’s completion tests scores (r = 0.409, p = 0.016; r = 0.341, p = 0.048 respectively). The proportion of white matter hyperintensities within the MR spectroscopy voxel did not correlate with the metabolite content. In this study, POWM metabolic alterations in DM1 patients were not associated with the white matter morphological changes and correlated with specific neuropsychological deficits.

Background:Pathological brain processes may induce adaptive cortical reorganization, however, the mechanisms underlying neuroplasticity that occurs in the presence of lesions in eloquent areas are not fully explained. The aim of this study was to evaluate functional compensatory cortical activations in patients with frontal brain gliomas during a phonemic fluency task and to explore correlations with cognitive performance, white matter tracts microstructural alterations, and tumor histopathological and molecular characterization.Methods:Fifteen patients with frontal glioma were preoperatively investigated with an MRI study on a 3T scanner and a subgroup underwent an extensive neuropsychological assessment. The hemispheric laterality index (LI) was calculated through phonemic fluency task functional MRI (fMRI) activations in the frontal, parietal, and temporal lobe parcellations. Diffusion-weighted images were acquired for all patients and for a group of 24 matched healthy volunteers. Arcuate Fasciculus (AF) and Frontal Aslant Tract (FAT) tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. All patients were operated on with a resective aim and underwent adjuvant therapies, depending on the final diagnosis.Results:All patients during the phonemic fluency task fMRI showed left hemispheric dominance in temporal and parietal regions. Regarding frontal regions (i.e., frontal operculum) we found right hemispheric dominance that increases when considering only those patients with tumors located on the left side. These latter activations positively correlate with verbal and visuo-spatial short-term memory, and executive functions. No correlations were found between the left frontal operculum and cognitive performance. Furthermore, patients with IDH-1 mutation and without TERT mutation, showed higher rightward frontal operculum fMRI activations and better cognitive performance in tests measuring general cognitive abilities, semantic fluency, verbal short-term memory, and executive functions. As for white matter tracts, we found left and right AF and FAT microstructural alterations in patients with, respectively, left-sided and right-side glioma compared to controls.Conclusions:Compensatory cortical activation of the corresponding region in the non-dominant hemisphere and its association with better cognitive performance and more favorable histopathological and molecular tumor characteristics shed light on the neuroplasticity mechanisms that occur in the presence of a tumor, helping to predict the rate of post-operative deficit, with the final goal of improving patients'quality of life.

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%–5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers’ germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.

Background: Tractography has been widely adopted to improve brain gliomas' surgical planning and guide their resection. This study aimed to evaluate state-of-the-art of arcuate fasciculus (AF) tractography for surgical planning and explore the role of along-tract analyses in vivo for characterizing tumor histopathology. Methods: High angular resolution diffusion imaging (HARDI) images were acquired for nine patients with tumors located in or near language areas (age: 41 ± 14 years, mean ± standard deviation; five males) and 32 healthy volunteers (age: 39 ± 16 years; 16 males). Phonemic fluency task fMRI was acquired preoperatively for patients. AF tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. Along-tract analyses were performed, dividing the AF into 15 segments along the length of the tract defined using the Laplacian operator. For each AF segment, diffusion tensor imaging (DTI) measures were compared with those obtained in healthy controls (HCs). The hemispheric laterality index (LI) was calculated from language task fMRI activations in the frontal, parietal, and temporal lobe parcellations. Tumors were grouped into low/high grade (LG/HG). Results: Four tumors were LG gliomas (one dysembryoplastic neuroepithelial tumor and three glioma grade II) and five HG gliomas (two grade III and three grade IV). For LG tumors, gross total removal was achieved in all but one case, for HG in two patients. Tractography identified the AF trajectory in all cases. Four along-tract DTI measures potentially discriminated LG and HG tumor patients (false discovery rate < 0.1): the number of abnormal MD and RD segments, median AD, and MD measures. Both a higher number of abnormal AF segments and a higher AD and MD measures were associated with HG tumor patients. Moreover, correlations (unadjusted p < 0.05) were found between the parietal lobe LI and the DTI measures, which discriminated between LG and HG tumor patients. In particular, a more rightward parietal lobe activation (LI < 0) correlated with a higher number of abnormal MD segments ( R = −0.732) and RD segments ( R = −0.724). Conclusions: AF tractography allows to detect the course of the tract, favoring the safer-as-possible tumor resection. Our preliminary study shows that along-tract DTI metrics can provide useful information for differentiating LG and HG tumors during pre-surgical tumor characterization.

Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%‐30%) presenting a rare large‐effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD‐associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole‐exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion‐transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only ( P = 6.07 × 10 −5 ). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low‐level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large‐effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders.

We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of neuroradiologic findings in routine magnetic resonance imaging (MRI) scans of a group of 117 ASD children younger than 5 years old. These data were compared to those reported in typically developing (TD) children. MRI findings in children with ASD were analyzed in relation to their cognitive level, severity of autistic symptoms, and the presence of electroencephalogram (EEG) abnormalities. The MRI was rated abnormal in 55% of children with ASD with a significant prevalence in the high-functioning subgroup compared to TD children. We report significant incidental findings of mega cisterna magna, ventricular anomalies and abnormal white matter signal intensity in ASD without significant associations between these MRI findings and EEG features. Based on these results we discuss the role that brain MRI may play in the diagnostic procedure of ASD.